Synthesis of Eosinophil Infiltration Inhibitors with Antihistaminic Activity
A series of [1, 2, 4]triazolo[1, 5-b]pyridazines (5) and imidazo[1, 2-b]pyridazines (6) having cyclic amines was synthesized and evaluated for antihistaminic activity and inhibitory effect on eosinophil infiltration. When a piperidine or a piperazine containing a benzhydryl group and a suitable spac...
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| Veröffentlicht in: | Chemical & pharmaceutical bulletin 2003, Vol.51(2), pp.122-133 |
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| creator | Gyoten, Michiyo Nagaya, Hideaki Fukuda, Shigeru Ashida, Yasuko Kawano, Yasuhiko |
| description | A series of [1, 2, 4]triazolo[1, 5-b]pyridazines (5) and imidazo[1, 2-b]pyridazines (6) having cyclic amines was synthesized and evaluated for antihistaminic activity and inhibitory effect on eosinophil infiltration. When a piperidine or a piperazine containing a benzhydryl group and a suitable spacer was incorporated at the 6-position, the fused pyridazines were found to exhibit both antihistaminic activity and an inhibitory effect on eosinophil chemotaxis. Above all, 6a showed potent antihistaminic activity, but little blockade of central H1 receptors in contrast with its complete blockade of peripheral H1 receptors as determined by an ex vivo binding assay. Furthermore, 6a inhibited eosinophil infiltration of the skin caused by a topical antigen challenge in sensitized guinea pigs, while an antihistamine terfenadine was not effective. After the pharmacokinetic study, 6a was found to be rapidly hydrolyzed to 6o, which was also orally active. Compound 6o, 2-[6-[[3-[4-(diphenylmethoxy)piperidino]propyl]amino]imidazo[1, 2-b]pyridazin-2-yl]-2-methylpropionic acid dihydrate (TAK-427), having both antihistaminic and antiinflammatory activity, is currently undergoing clinical trials as a therapeutic agent for atopic dermatitis and allergic rhinitis. |
| doi_str_mv | 10.1248/cpb.51.122 |
| format | Article |
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When a piperidine or a piperazine containing a benzhydryl group and a suitable spacer was incorporated at the 6-position, the fused pyridazines were found to exhibit both antihistaminic activity and an inhibitory effect on eosinophil chemotaxis. Above all, 6a showed potent antihistaminic activity, but little blockade of central H1 receptors in contrast with its complete blockade of peripheral H1 receptors as determined by an ex vivo binding assay. Furthermore, 6a inhibited eosinophil infiltration of the skin caused by a topical antigen challenge in sensitized guinea pigs, while an antihistamine terfenadine was not effective. After the pharmacokinetic study, 6a was found to be rapidly hydrolyzed to 6o, which was also orally active. Compound 6o, 2-[6-[[3-[4-(diphenylmethoxy)piperidino]propyl]amino]imidazo[1, 2-b]pyridazin-2-yl]-2-methylpropionic acid dihydrate (TAK-427), having both antihistaminic and antiinflammatory activity, is currently undergoing clinical trials as a therapeutic agent for atopic dermatitis and allergic rhinitis.</description><identifier>ISSN: 0009-2363</identifier><identifier>EISSN: 1347-5223</identifier><identifier>DOI: 10.1248/cpb.51.122</identifier><identifier>PMID: 12576644</identifier><identifier>CODEN: CPBTAL</identifier><language>eng</language><publisher>Tokyo: The Pharmaceutical Society of Japan</publisher><subject>Animals ; antihistaminic activity ; atopic dermatitis ; Biological and medical sciences ; brain penetrability ; eosinophil infiltration ; Eosinophils - cytology ; Eosinophils - drug effects ; Guinea Pigs ; Histamine and antagonists. Allergy ; Histamine H1 Antagonists - chemical synthesis ; Histamine H1 Antagonists - pharmacology ; imidazo[1,2-b]pyridazine ; Male ; Medical sciences ; Pharmacology. Drug treatments ; structure–activity relationship ; Trachea - cytology ; Trachea - drug effects ; Trachea - metabolism</subject><ispartof>Chemical and Pharmaceutical Bulletin, 2003, Vol.51(2), pp.122-133</ispartof><rights>2003 The Pharmaceutical Society of Japan</rights><rights>2003 INIST-CNRS</rights><rights>Copyright Japan Science and Technology Agency 2003</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c499t-96c053c6d5cb46a8b664d6cfd7060be92775b39e24a13559a465585057915a5c3</citedby><cites>FETCH-LOGICAL-c499t-96c053c6d5cb46a8b664d6cfd7060be92775b39e24a13559a465585057915a5c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1881,27915,27916</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14569919$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12576644$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gyoten, Michiyo</creatorcontrib><creatorcontrib>Nagaya, Hideaki</creatorcontrib><creatorcontrib>Fukuda, Shigeru</creatorcontrib><creatorcontrib>Ashida, Yasuko</creatorcontrib><creatorcontrib>Kawano, Yasuhiko</creatorcontrib><title>Synthesis of Eosinophil Infiltration Inhibitors with Antihistaminic Activity</title><title>Chemical & pharmaceutical bulletin</title><addtitle>Chem. Pharm. Bull.</addtitle><description>A series of [1, 2, 4]triazolo[1, 5-b]pyridazines (5) and imidazo[1, 2-b]pyridazines (6) having cyclic amines was synthesized and evaluated for antihistaminic activity and inhibitory effect on eosinophil infiltration. When a piperidine or a piperazine containing a benzhydryl group and a suitable spacer was incorporated at the 6-position, the fused pyridazines were found to exhibit both antihistaminic activity and an inhibitory effect on eosinophil chemotaxis. Above all, 6a showed potent antihistaminic activity, but little blockade of central H1 receptors in contrast with its complete blockade of peripheral H1 receptors as determined by an ex vivo binding assay. Furthermore, 6a inhibited eosinophil infiltration of the skin caused by a topical antigen challenge in sensitized guinea pigs, while an antihistamine terfenadine was not effective. After the pharmacokinetic study, 6a was found to be rapidly hydrolyzed to 6o, which was also orally active. Compound 6o, 2-[6-[[3-[4-(diphenylmethoxy)piperidino]propyl]amino]imidazo[1, 2-b]pyridazin-2-yl]-2-methylpropionic acid dihydrate (TAK-427), having both antihistaminic and antiinflammatory activity, is currently undergoing clinical trials as a therapeutic agent for atopic dermatitis and allergic rhinitis.</description><subject>Animals</subject><subject>antihistaminic activity</subject><subject>atopic dermatitis</subject><subject>Biological and medical sciences</subject><subject>brain penetrability</subject><subject>eosinophil infiltration</subject><subject>Eosinophils - cytology</subject><subject>Eosinophils - drug effects</subject><subject>Guinea Pigs</subject><subject>Histamine and antagonists. Allergy</subject><subject>Histamine H1 Antagonists - chemical synthesis</subject><subject>Histamine H1 Antagonists - pharmacology</subject><subject>imidazo[1,2-b]pyridazine</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>structure–activity relationship</subject><subject>Trachea - cytology</subject><subject>Trachea - drug effects</subject><subject>Trachea - metabolism</subject><issn>0009-2363</issn><issn>1347-5223</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpd0E1rGzEQBmARGhI3zaU_oCyU9hDYVF-jtU7FhDQNGHJocxZaWdsds5ZcSW7xv6-C3Rp6kUboYWZ4CXnL6C3jcv7JbftbYLXmZ2TGhOxa4Fy8IjNKqW65UOKSvM55TSkH2okLcsk4dEpJOSPLb_tQRp8xN3Fo7mPGELcjTs1jGHAqyRaMoT5G7LHElJvfWMZmEQqOmIvdYEDXLFzBX1j2b8j5YKfsr4_3FXn-cv_97mu7fHp4vFssWye1Lq1WjoJwagWul8rO-7rKSrlh1VFFe69510EvtOfSMgGgrVQAc6DQaQYWnLgiHw99tyn-3PlczAaz89Nkg4-7bDpBKXCpK3z_H1zHXQp1N8OkokJxpVhVNwflUsw5-cFsE25s2htGzUvCpiZsgNWaV_zu2HLXb_zqRI-RVvDhCGx2dhqSDQ7zyUlQWrOX3T4f3Lrm-MP_AzYVdJP_O5Mfjjr69DPaZHwQfwACvJlL</recordid><startdate>20030201</startdate><enddate>20030201</enddate><creator>Gyoten, Michiyo</creator><creator>Nagaya, Hideaki</creator><creator>Fukuda, Shigeru</creator><creator>Ashida, Yasuko</creator><creator>Kawano, Yasuhiko</creator><general>The Pharmaceutical Society of Japan</general><general>Maruzen</general><general>Japan Science and Technology Agency</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20030201</creationdate><title>Synthesis of Eosinophil Infiltration Inhibitors with Antihistaminic Activity</title><author>Gyoten, Michiyo ; Nagaya, Hideaki ; Fukuda, Shigeru ; Ashida, Yasuko ; Kawano, Yasuhiko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c499t-96c053c6d5cb46a8b664d6cfd7060be92775b39e24a13559a465585057915a5c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>antihistaminic activity</topic><topic>atopic dermatitis</topic><topic>Biological and medical sciences</topic><topic>brain penetrability</topic><topic>eosinophil infiltration</topic><topic>Eosinophils - cytology</topic><topic>Eosinophils - drug effects</topic><topic>Guinea Pigs</topic><topic>Histamine and antagonists. Allergy</topic><topic>Histamine H1 Antagonists - chemical synthesis</topic><topic>Histamine H1 Antagonists - pharmacology</topic><topic>imidazo[1,2-b]pyridazine</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>structure–activity relationship</topic><topic>Trachea - cytology</topic><topic>Trachea - drug effects</topic><topic>Trachea - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gyoten, Michiyo</creatorcontrib><creatorcontrib>Nagaya, Hideaki</creatorcontrib><creatorcontrib>Fukuda, Shigeru</creatorcontrib><creatorcontrib>Ashida, Yasuko</creatorcontrib><creatorcontrib>Kawano, Yasuhiko</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Chemical & pharmaceutical bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gyoten, Michiyo</au><au>Nagaya, Hideaki</au><au>Fukuda, Shigeru</au><au>Ashida, Yasuko</au><au>Kawano, Yasuhiko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis of Eosinophil Infiltration Inhibitors with Antihistaminic Activity</atitle><jtitle>Chemical & pharmaceutical bulletin</jtitle><addtitle>Chem. Pharm. Bull.</addtitle><date>2003-02-01</date><risdate>2003</risdate><volume>51</volume><issue>2</issue><spage>122</spage><epage>133</epage><pages>122-133</pages><issn>0009-2363</issn><eissn>1347-5223</eissn><coden>CPBTAL</coden><abstract>A series of [1, 2, 4]triazolo[1, 5-b]pyridazines (5) and imidazo[1, 2-b]pyridazines (6) having cyclic amines was synthesized and evaluated for antihistaminic activity and inhibitory effect on eosinophil infiltration. When a piperidine or a piperazine containing a benzhydryl group and a suitable spacer was incorporated at the 6-position, the fused pyridazines were found to exhibit both antihistaminic activity and an inhibitory effect on eosinophil chemotaxis. Above all, 6a showed potent antihistaminic activity, but little blockade of central H1 receptors in contrast with its complete blockade of peripheral H1 receptors as determined by an ex vivo binding assay. Furthermore, 6a inhibited eosinophil infiltration of the skin caused by a topical antigen challenge in sensitized guinea pigs, while an antihistamine terfenadine was not effective. After the pharmacokinetic study, 6a was found to be rapidly hydrolyzed to 6o, which was also orally active. Compound 6o, 2-[6-[[3-[4-(diphenylmethoxy)piperidino]propyl]amino]imidazo[1, 2-b]pyridazin-2-yl]-2-methylpropionic acid dihydrate (TAK-427), having both antihistaminic and antiinflammatory activity, is currently undergoing clinical trials as a therapeutic agent for atopic dermatitis and allergic rhinitis.</abstract><cop>Tokyo</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>12576644</pmid><doi>10.1248/cpb.51.122</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals antihistaminic activity atopic dermatitis Biological and medical sciences brain penetrability eosinophil infiltration Eosinophils - cytology Eosinophils - drug effects Guinea Pigs Histamine and antagonists. Allergy Histamine H1 Antagonists - chemical synthesis Histamine H1 Antagonists - pharmacology imidazo[1,2-b]pyridazine Male Medical sciences Pharmacology. Drug treatments structure–activity relationship Trachea - cytology Trachea - drug effects Trachea - metabolism |
| title | Synthesis of Eosinophil Infiltration Inhibitors with Antihistaminic Activity |
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